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[Preprint]. 2020 Dec 21:2020.12.18.20248226.
doi: 10.1101/2020.12.18.20248226.

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19

Gundula Povysil  1 , Guillaume Butler-Laporte  2   3 , Ning Shang  4 , Chen Weng  4 , Atlas Khan  4 , Manal Alaamery  5   6   7 , Tomoko Nakanishi  2   8   9   10 , Sirui Zhou  2 , Vincenzo Forgetta  2 , Robert Eveleigh  11   12 , Mathieu Bourgey  11   12 , Naveed Aziz  13 , Steven Jones  13 , Bartha Knoppers  13 , Stephen Scherer  13 , Lisa Strug  13 , Pierre Lepage  11 , Jiannis Ragoussis  8   11 , Guillaume Bourque  8   12   11 , Jahad Alghamdi  14 , Nora Aljawini  5   6   7 , Nour Albes  5   6   15 , Hani M Al-Afghani  16 , Bader Alghamdi  5 , Mansour Almutair  5 , Ebrahim Sabri Mahmoud  7 , Leen Abu Safie  17 , Hadeel El Bardisy  17 , Fawz S Al Harthi  17 , Abdulraheem Alshareef  16 , Bandar Ali Suliman  18 , Saleh Alqahtani  18   19 , Abdulaziz AlMalik  20 , May M Alrashed  21 , Salam Massadeh  5   6   7 , Vincent Mooser  8 , Mark Lathrop  8   13   11 , Yaseen Arabi  7   15 , Hamdi Mbarek  22 , Chadi Saad  22 , Wadha Al-Muftah  22 , Radja Badji  22 , Asma Al Thani  22 , Said I Ismail  22 , Ali G Gharavi  1   4   23 , Malak S Abedalthagafi  17   20 , J Brent Richards  2   3   8   24 , David B Goldstein  1   25 , Krzysztof Kiryluk  1   4
Affiliations

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19

Gundula Povysil et al. medRxiv. .

Update in

  • Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19.
    Povysil G, Butler-Laporte G, Shang N, Wang C, Khan A, Alaamery M, Nakanishi T, Zhou S, Forgetta V, Eveleigh RJ, Bourgey M, Aziz N, Jones SJ, Knoppers B, Scherer SW, Strug LJ, Lepage P, Ragoussis J, Bourque G, Alghamdi J, Aljawini N, Albes N, Al-Afghani HM, Alghamdi B, Almutairi MS, Mahmoud ES, Abu-Safieh L, El Bardisy H, Harthi FSA, Alshareef A, Suliman BA, Alqahtani SA, Almalik A, Alrashed MM, Massadeh S, Mooser V, Lathrop M, Fawzy M, Arabi YM, Mbarek H, Saad C, Al-Muftah W, Jung J, Mangul S, Badji R, Thani AA, Ismail SI, Gharavi AG, Abedalthagafi MS, Richards JB, Goldstein DB, Kiryluk K. Povysil G, et al. J Clin Invest. 2021 Jul 15;131(14):e147834. doi: 10.1172/JCI147834. J Clin Invest. 2021. PMID: 34043590 Free PMC article.

Abstract

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.

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Figures

Figure 1.
Figure 1.. Power curves for a gene set based collapsing test:
Power calculations for the Columbia COVID-19 Biobank cohort of 480 severe COVID-19 cases and 9,589 population controls were performed using the samplesizeCMH R package (version 0.0.0) for a dominant model at alpha=0.05 and a range of odds ratios (OR). Results are shown for the pLOF and model including pLOFs and missense model. Since power is influenced by the carrier frequency, we have adequate power to detect effect sizes as small as 1.5 for the model including missense variants compared to 5.5 for the rare pLOF variants only model.
See this image and copyright information in PMC

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